This renewal for years 21-25 describes experiments aimed at understanding the structural organization of the mesocortices that form the limbic lobe of the human and non-human primate brain. Such experiments are essential for ascertaining the contributions of mesocortical areas to processes like learning and memory, emotion and motivation. They define the playing field, for both basic science functional efforts using experimental animals, and clinical science functional efforts using behavioral and functional imaging methods in humans. Neurological diseases, such as Alzheimer's disease and temporal lobe epilepsy target the mesocortices as do psychiatric and developmental diseases such as schizophrenia and autism. Aim 1 will investigate the organization of theperforant pathway in the human brain capitalizing on the entorhinal neurofibrillary tangle lesion of Alzheimer's disease which renders its degenerating terminals immunoreactive for the abnormally phosphorylated tau protein molecule. This lesion also induces sprouting in the perforant pathway terminal zone which is detectable with enzyme and cell adhesion molecule staining. Thus, multiple methods will reveal both degeneration, and the brains response to it, and outline this neural system critical for memory. Aim 2 will investigate the microvascular capillary supply to the cells of origin for the perforant pathway of the human brain. It will reveal that these neurons are enmeshed in a unique capillary syncitium to support their high metabolic and excitatory activity. Results will lay the groundwork for functional imaging investigations in the human. Aim 3 will investigate the nature of identified cortical input to the neurons of origin of the perforant pathway in the monkey and capitalize on Lucifer yellow intracellular filling for phenotype identity. Confocal laser scanning microscopy will reveal synaptophysin marked presynaptic terminals on connection identified perforant pathway neurons. All aims address the general theme of entorhinal cortical modularity and draw on a variety of methods and two primate species. This research will be conducted in a laboratory with a long history devoted to understanding structural and functional relationships in the primate brain, and the disruption of these relationships in neurological disease. It is interactive research that draws on a large body of data gathered over 31 years at Harvard Medical School (1969-1978) and The University of Iowa (1979-present).